Extreme obesity induces massive beta cell expansion in mice through self-renewal and does not alter the beta cell lineage

Abstract

Aims/hypothesis: Understanding the developmental biology of beta cell regeneration is critical for developing new diabetes therapies. Obesity is a potent but poorly understood stimulus for beta cell expansion. Current models of obesity are complicated by developmental compensation or concurrent diabetes, limiting their usefulness for identifying the lineage mechanism(s) of beta cell expansion. We aimed to determine whether acute inducible obesity stimulates beta cell expansion and to determine the lineage mechanism of beta cell growth in obesity. Methods: We created whole-body tamoxifen-inducible leptin receptor (LepR)-deficient mice (Ubc-CreERT2LepRloxP/loxP) as a novel model of acute obesity. Beta cell mass and proliferation were quantified after short-term LepR deletion. Clonal analysis of beta cell expansion using the Brainbow2.1 reporter was performed 6 months post tamoxifen initiation. Results: LepR deficiency induced a doubling of body mass within 3 weeks, with moderate glucose intolerance (unlike typical LepR mutant mice [db/db], which have frank diabetes). Beta cell mass expanded threefold through increased beta cell proliferation, without evidence for contribution from specialised progenitors or stem cells (via sequential thymidine labelling and Brainbow2.1 reporter). Thus, self-renewal is the primary lineage mechanism in obesity-induced beta cell expansion. However, even the rapid beta cell proliferation could not exceed the restrictions of the replication refractory period. Conclusions/interpretation: In summary, we created a novel model of inducible obesity demonstrating that even extreme metabolic demand does not alter beta cell lineage.